Geniposide Improves Glucose Homeostasis via Regulating FoxO1/PDK4 in Skeletal Muscle

J Agric Food Chem. 2019 Apr 24;67(16):4483-4492. doi: 10.1021/acs.jafc.9b00402. Epub 2019 Apr 10.

Abstract

It is well-known that imbalance state of glucose metabolism triggers many metabolic diseases and glucose uptake in skeletal muscle accounts for 90% of body weight. Geniposide is one of the major natural bioactive constituents of gardenia fruit, and the regulation of geniposide on glucose metabolism in skeletal muscle has not yet been investigated. Here, on the basis of microarray analysis, we discovered that geinposide decreased pyruvate dehydrogenase kinase 4 (PDK4) expression in skeletal muscle of mice and subsequently found that geniposide inhibited the expressions of forkhead box O1 (FoxO1), PDK4, and phosphorylated pyruvate dehydrogenase in vitro and in vivo. Moreover, geniposide promoted a switch of slow-to-fast myofiber type and glucose utilization, suggesting that geniposide improved glucose homeostasis. In addition, mechanistic studies revealed that geniposide played above roles by regulating FoxO1/PDK4, which controlled fuel selection via pyruvate dehydrogenase. Meanwhile, effects of geniposide mentioned above could be reversed by FoxO1 overexpression. Together, these results establish that geniposide confers controls on fuel usage and glucose homeostasis through FoxO1/PDK4 in skeletal muscle.

Keywords: FoxO1; PDK4; geniposide; glucose utilization; skeletal muscle.

MeSH terms

  • Animals
  • Diabetes Mellitus, Type 2 / drug therapy*
  • Diabetes Mellitus, Type 2 / genetics
  • Diabetes Mellitus, Type 2 / metabolism
  • Forkhead Box Protein O1 / genetics
  • Forkhead Box Protein O1 / metabolism*
  • Glucose / metabolism*
  • Homeostasis / drug effects
  • Humans
  • Iridoids / administration & dosage*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Muscle Fibers, Skeletal / drug effects
  • Muscle Fibers, Skeletal / metabolism
  • Muscle, Skeletal / metabolism*
  • Phosphorylation / drug effects
  • Protein Kinases / genetics
  • Protein Kinases / metabolism*
  • Signal Transduction / drug effects
  • Up-Regulation / drug effects

Substances

  • Forkhead Box Protein O1
  • Foxo1 protein, mouse
  • Iridoids
  • geniposide
  • Protein Kinases
  • pyruvate dehydrogenase kinase 4
  • Glucose